Life expectancy among American Indians and Alaska Natives (AI/ANs) has declined from 72 years in 2019 to 68 years in 2021. This current life expectancy for AI/ANs is equivalent to the overall life expectancy in the United States population in the 1940s. The significant and persistent nature of AI/AN health inequities, and the lack of clarity around what is driving them, requires urgent action. The purpose of this article is threefold. First, we provide a comprehensive conceptual framework of health that presents Indigenous perspectives of health and recognizes settler colonialism as a key structural determinant of the health of AI/ANs. Second, we underscore the importance of Tribal self-determination and sovereignty in public health research and practice and identify successful initiatives centering these efforts. Finally, we conclude with recommendations for future research, practice, and policy.